Mitotic kinases safeguarding genome stability during mammalian cell division

About the project

About the Project Faithful cell division ensures the correct segregation of the genetic material over multiple generations. Failure of this process may result in cell death or lay the foundation for tumorigenesis. An important prerequisite for successful chromosome segregation and maintenance of genomic integrity is the correct attachment of the chromosomes to microtubules, enabling faithful partitioning of the genetic material. The fidelity of this process is achieved through the combined actions of the so-called error correction process and the spindle assembly checkpoint, crucial molecular safe-guarding mechanisms that jointly eliminate erroneous microtubule-kinetochore attachments and promote bipolar chromosome orientation critical for faithful cell division. In my research group, we aim to understand the molecular mechanisms underpinning the accurate segregation of the chromosomes in mammalian cells, and what aspects of these processes are changed in cancer cells which often have higher, aneuploid, numbers of chromosomes than their non-transformed counterparts. Dynamic phosphorylation is a particularly important control mechanism for the chromosome segregation process. Pericentromeric Aurora B and kinetochore-localised MPS1 are key mitotic kinases jointly orchestrating error correction and the spindle assembly checkpoint. We now seek to understand how the spatial arrangement of these kinases at different stages of mitosis regulates their interaction and the processes they control. To achieve this, we will employ a combination of biochemical and cell biological techniques, including quantitative fixed and live cell imaging, CRISPR/Cas9-mediated genetic manipulation of cells, in vitro reconstitution assays and protein-protein interaction analysis by mass spectrometry.

Research areas